Phosphatidylinositol 3-kinases (PI3K) phosphorylate phosphinositides at the 3-hydroxyl. These enzymes generate second messengers (for example, PIP3) and act as transducers downstream of tyrosine kinase receptors and G-protein coupled receptors. The PI3Ks are involved in a large number of fundamental processes including apoptosis, proliferation, cell motility, and adhesion. (see Walker et al., Molec. Cell 6:909-919, 2000). Thus, several PI3K inhibitors have been developed.
Mammalian Target of Rapamycin (mTOR) is a 289 kDa serine threonine kinase that is also known as FKBP-12 target-1 (RAFT-1) and FKBP-12 rapamycin associated protein. There are several conserved domains of mTOR, including a serine-threonine kinase domain. T cell models suggest that IL-2 and other factors promote mTOR activation and subsequently promote cell growth by inducing new protein synthesis. mTOR is known to contribute to the activation of P70 S6 kinases, which in turn catalyze phosphorylation of S6, a 40S ribosomal protein required for activating polysomes to drive protein synthesis and mRNA translation. In addition, mTOR activates the eukaryotic initiation factor 4E. Thus, mTOR plays a role in regulating protein synthesis and the cell cycle. It is believed that mTOR acts as a checkpoint by sensing cell status and regulating cell progress through the G1-S phase. Various known effector pathways upstream and downstream of mTOR are used to regulate mTOR activities. Thus, compounds that inactivate MTOR by binding to mTOR can be used to regulate cell cycle function, and thereby cell growth. As mTOR specifically functions in lymphocytes, inhibition of mTOR can also be used to alter signaling in T and B cells (see Kirken and Want, Transplantation Proc. 35:227S-230S, 2003).
Known mTOR inhibitors include LY294002 (2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one) and rapamycin. Rapamycin is used in immunosuppression, chemotherapeutic protocols, and in the prevention of post-angioplasty coronary restenosis. LY294002 blocks PI3K-dependent phosphorylation of protein kinase B. Rapamycin has significant adverse effects, including hypercholesterolemia, drug-induced pheumonitis, renal toxicity, hypertension, and increasing the predisposition to opportunistic infections.
Undesired cell proliferation is a component of many disease processes. For example, undesired cell growth can lead to the formation of either benign or malignant tumors. According to the American Cancer Society, cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. If the spread is not controlled, it can result in death. Although cancer is often referred to as a single condition, it actually consists of more than 100 different diseases. These diseases are characterized by uncontrolled growth and spread of abnormal cells. Cancer can arise in many sites and behave differently depending on its organ of origin. There is a continued search for agents of use in the treatment of the different types of cancer.
Undesired cell growth is also a component of restenosis, the recurrence of stenosis or artery stricture after corrective surgery. Restenosis occurs after coronary artery bypass (CAB), endarterectomy, heart transplantation, and particularly after angioplasty, atherectomy, laser ablation or stenting. Restenosis is the result of injury to the blood vessel wall during the lumen opening procedure. In some patients, the injury initiates a repair response that is characterized by smooth muscle cell proliferation referred to as “hyperplasia” in the region traumatized by the angioplasty. This proliferation of smooth muscle cells re-narrows the lumen that was opened by the angioplasty within a few weeks to a few months, thereby necessitating a repeat angioplasty or other procedure to alleviate the restenosis.
In an immune response, T and or B cells proliferate in response to a stimulus viewed as “exogenous” by the immune system. Although generally immune responses are beneficial, there are situations where a decreased immune response is desired. For example, in autoimmune disorders, the cells of the immune system incorrectly identify a self component as exogenous and proliferate in response to the self component. Inflammatory responses can be deleterious, as can immune responses against a transplanted organ.
There is clearly a need to develop agents that can reduce undesired cellular proliferation. These agents include agents that induce immunosuppression, chemotherapeutics, and agents for the treatment of restenosis.